Mechanisms and Application Strategies of Flavonoid Active Compounds in the Treatment of Osteoporosis-Osteoarthritis Comorbidity: Insights from Preclinical Studies.

Osteoporosis (OP) and osteoarthritis (OA) are two prevalent age-related musculoskeletal disorders that frequently coexist in elderly populations, substantially complicating clinical diagnosis and treatment. In recent years, flavonoid active compounds have attracted increasing research interest for OP-OA comorbidity owing to their multitargeted pharmacological activities and generally favorable safety profiles, although current evidence remains largely limited to preclinical in vitro and animal studies. This review systematically summarizes the chemical classification, natural sources and pharmacokinetic profiles of flavonoids, and dissects the pathophysiological crosstalk underlying OP-OA comorbidity, focusing on core cascades including estrogen deficiency, chronic inflammation, oxidative stress and dysregulation of shared signaling pathways. We collate preclinical evidence from animal models and cell experiments regarding representative flavonoids (icariin, quercetin, liquiritigenin, soy isoflavones, and others) for concurrent OP and OA, and delineate their molecular mechanisms: modulation of antioxidant and anti-inflammatory responses; balancing bone metabolism via OPG/RANKL/RANK, PI3K/Akt and Wnt/beta-catenin axes; attenuating cartilage degeneration and intra-articular inflammation; and multitargeted regulation of MAPK, NF-kappaB and Hippo pathways. Key findings indicate that flavonoids exert preclinical protective effects through coordinated modulation of shared pathological axes, yet several critical gaps remain: effective in vitro concentrations (25-100 microM) far exceed achievable in vivo plasma levels, most evidence derives from single-disease rather than bona fide comorbidity models, and high-quality clinical trials are lacking. Strategies including bioavailability enhancement, bone- or joint-targeted nanodelivery, and combinatorial regimens are discussed as avenues to bridge these gaps. Flavonoids show promising preclinical potential for OP-OA comorbidity; however, their efficacy and safety require further validation in standardized comorbidity animal models, high-quality pharmacokinetic studies, and well-designed clinical trials before clinical application can be recommended.